Essential tremor (ET) is one of the most common neurological diseases yet it is also among the least studied. Few medications treat the disorder, which is usually progressive. Although it is as much as twenty times more prevalent than Parkinson's disease, at the time of our original application (2002), we noted that there were only 15 postmortems, most of which were from the pre-modern era. Hence, there was almost no knowledge of the underlying pathology of ET. Although often reiterated that 'there is no pathology' in ET, this was not based on rigorous study. Since 2003, our goal has been to establish the Essential Tremor Centralized Brain Repository to address a fundamental question in ET research: can an underlying pathology be identified in terms of morphological changes in specific brain regions? After intensively collecting and then studying 51 ET brains and 34 control brains, we have discovered that, indeed, there are identifiable pathological changes in the ET brain: 82.3% of ET brains have cerebellar degenerative changes in the form of increased numbers of torpedoes and mild reduction in Purkinje cell (PC) number (cerebellar ET) whereas 17.7% have brainstem Lewy bodies. Hence, at this point, we have described several basic changes in the ET brain. Clinical differences between the two pathologically-identified subtypes of ET have not been well studied. We now wish to move beyond our initial work. SPECIFIC AIM 1 is to advance our knowledge of the postmortem changes in patients with cerebellar ET (Aim 1A) and Lewy body ET (Aim 1B) through detailed studies of PC neuronal morphology. In Aim 1A, we will also begin to study neurofilament proteins. Because our previous analyses were confined to a single region of one cerebellar hemisphere, we will broaden our scope to include each of the other functional-anatomic regions of the cerebellum (Aim 1C). In Aim 1D, we will extend our analyses to the thalamus. SPECIFIC AIM 2 is to establish basic links between clinical features and postmortem brain changes (clinical-pathological correlation). The clinical evaluation in our 2002 application was, by design, brief and indirect (telephone and videotape). Now our aim is to conduct a comprehensive in- person clinical evaluation of 175 elderly ET cases, 44 of whom we expect to die during this five year proposal. In doing so, we can begin to identify the specific clinical features that characterize patients with each of the two pathological subtypes of ET. Our goal is to advance this field by: (1) increasing our understanding of the pathological anatomy of ET, and (2) forging the needed links between what physicians observe in living patients and what we uncover in detailed postmortem studies. PUBLIC HEALTH RELEVANCE Essential tremor (ET) is among the most common neurological diseases, yet until recently there had been very few postmortem studies. After intensively collecting and studying 51 ET brains and 34 control brains over the past 5 years, we have discovered that, indeed, there are identifiable pathological changes in the ET brain. Our aims in this competitive renewal application are to advance our knowledge of the postmortem changes in ET with more detailed quantitative morphological studies of Purkinje cells (Aim 1) and to establish basic links between clinical features and postmortem brain changes (Aim 2). Our tissue-based research will place us in unique a position to begin to address basic mechanistic questions about ET and may allow treating physicians to predict during life which subtype of ET a patient is likely to have.